Camptothecin, a plant alkaloid isolated from trees indigenous to China, and analogues thereof such as 9-aminocamptothecin, 10-hydroxycamptothecin, 10,11-methylenedioxycamptothecin, 9-nitro-10,11-methylenedioxycamptothecin, 9-chloro-10,11-methylenedioxycam ptothecin, 9-amino-10,11-methylenedioxycamptothecin, 9-nitrocamptothecin, topotecan, and other analogues (collectively referred to herein as "camptothecin drugs") are presently under study worldwide in research laboratories and cancer clinics. In lab tests and in clinical trials, the camptothecin drugs have aroused considerable interest as a result their ability to halt the growth of a wide range of human tumors. For example, these drugs exhibit unprecedented high levels of antitumor activities against human colon cancer, Giovanella, et al. Science 246: 1046-1048 (Washington, D.C.) (1989). Camptothecin has also been shown to be effective against other experimental cancer types such as lung, breast, and malignant melanoma.
Camptothecin is thought to inhibit the proliferation of cancer cells by interfering with the breakage/reunion reaction of the enzyme topoisomerase I, a nuclear enzyme implicated in DNA replication and RNA transcription. The camptothecin stabilizes and forms a reversible enzyme-camptothecin-DNA ternary complex, designated the "cleavage complex". The formation of the cleavable complex specifically prevents the reunion step of the breakage/union cycle of the topoisomerase reaction.
However, the clinical use of the camptothecin drugs is limited by their chemical properties. First, the camptothecin drugs are insoluble in water which hinders the delivery of the drug to the cancer cells. Second, the camptothecin drugs are extremely susceptible to hydrolysis; in an aqueous environment such as blood plasma, the half life is about 16 to 29 minutes. The camptothecin drugs each contain a substituted quinoline nucleus (rings A-C) and, at the opposite end an .alpha.-hydroxy lactone ring which is very unstable in aqueous environments. In blood plasma the ring is quickly opened to create the carboxylate form of the drug, which is poorly accumulated by cancer cells. Once internalized by the cancer cells, the carboxylate form exhibits no activity against its molecular target, topoisomersase I. Thus, The hydrolysed product is ineffective at treating cancer. Moreover, the hydrolysed product appears to be more toxic to healthy tissue than the camptothecin drugs.
Attempts have been made to improve the clinical utility of the camptothecin drugs by modifying the chemical structure of the camptothecin drugs. Specifically, attempts have been made to increase the water solubility of the camptothecin drugs by introducing additional hydroxyl groups on the camptothecin drug molecules. While such modifications have improved the water solubility of the camptothecin drugs, they have had the concomitant effect of decreasing the pharmacological activity of the drugs.
It is desirable to have camptothecin drugs that are stable, water soluble, relatively non toxic, that still maintain antitumor activity.